F. M. Singer et al., Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Endo et al in U.S. Pat. Nos. 4,049,495, 4,137,322 and 3,983,140 disclose a fermentation product which is active in the inhibition of cholesterol biosynthesis. This product is called compactin and was reported by Brown et al., (J. Chem. Soc. Perkin I. 1165 (1976)) to have a complex mevalonolactone structure.
GB 1,586,152 discloses a group of synthetic compounds of the formula ##STR3## in which E represents a direct bond, a C.sub.1-3 alkylene bridge or a vinylene bridge and the various R's represent a variety of substituents.
The activity reported in the U.K. patent is less than 1% that of compactin.
U.S. Pat. No. 4,375,475 to Willard et al discloses hypocholesterolemic and hypolipemic compounds having the structure ##STR4## wherein A is H or methyl; E is a direct bond, --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 -- or --CH.dbd.CH--; R.sub.1, R.sub.2 and R.sub.3 are each selected from H, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, phenyl, phenyl substituted by halogen, C.sub.1-4 alkoxy, C.sub.2-8 alkanoyloxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl, and OR.sub.4 in which R.sub.4 is H, C.sub.2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl C.sub.1-3 alkyl, C.sub.1-9 alkyl, cinnamyl, C.sub.1-4 haloalkyl, allyl, cycloalkyl-C.sub.1-3 -alkyl, adamantyl-C.sub.1-3 -alkyl, or substituted phenyl C.sub.1-3 -alkyl in each of which the substituents are selected from halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of said acids, and the C.sub.1-3 alkyl and phenyl, dimethylamino or acetylamino substituted C.sub.1-3 -alkyl esters of the dihydroxy acids; all of the compounds being the enantiomers having a 4 R configuration in the tetrahydropyran moiety of the trans racemate shown in the above formula.
WO 84/02131 (PCT/EP83/00308) (based on U.S. application Ser. No. 443,668, filed Nov. 22, 1982, and U.S. application Ser. No. 548,850, filed Nov. 4, 1983), filed in the name of Sandoz A. G. discloses heterocyclic analogs of mevalono lactone and derivatives thereof having the structure ##STR5## wherein one of R and R.sub.o is ##STR6## and the other is primary or secondary C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or phenyl--(CH.sub.2).sub.m --,
wherein R.sub.4 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.5a is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and PA1 m is 1, 2 or 3, PA1 with the provisos that both R.sub.5 and R.sub.5a must be hydrogen when R.sub.4 is hydrogen, R.sub.5a must be hydrogen when R.sub.5 is hydrogen, not more than one of R.sub.4 and R.sub.5 is trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy and not more than one of R.sub.4 and R.sub.5 is benzyloxy, PA1 R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R.sub.3 must be hydrogen when R.sub.2 is hydrogen, not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and R.sub.3 is benzyloxy. PA1 Pr=a carbinol-protecting group; PA1 R.sup.1 =H or CH.sub.3 ; PA1 R.sup.3, R.sup.4 =H, 1-3C alkyl or phenyl-(1-3C alkyl), the phenyl being optionally substituted by 1-3C alkyl, 1-3C alkoxy or halo; PA1 R.sup.2 =a group of formula (A) or (B): ##STR11## Q= ##STR12## R.sup.6 =H or OH; R=H or CH.sub.3 ; PA1 a, b, c and d=optional double bonds; PA1 R.sup.7 =phenyl or benzyloxy, the ring in each case being optionally substituted by 1-3C alkyl or halo; PA1 R.sup.8, R.sup.9 =1-3C alkyl or halo; PA1 R.sup.5 =1-3C alkyl, phenyl or mono- or di-(1-3C alkyl)phenyl. PA1 R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and R.sub.3 is benzyloxy, PA1 R.sub.1 is hydrogen, C.sub.1-6 alkyl, fluoro, chloro or benzyloxy, PA1 R.sub.4 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.5a is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and with the provisos that not more than one of R.sub.4 and R.sub.5 is trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy and not more than one of R.sub.4 and R.sub.5 is benzyloxy, PA1 X is ##STR16## wherein n is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1, PA1 Z is ##STR17## wherein R.sub.6 is hydrogen or C.sub.1-3 alkyl, with the general proviso that --X--Z and the R.sub.4 bearing phenyl group are ortho to each other; PA1 in free acid form or in the form of a physiologically-hydrolysable and acceptable ester or a .delta. lactone thereof or in salt form. PA1 each of R.sub.2 and R.sub.5 is independently hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenyl, phenoxy or benzyloxy, PA1 each of R.sub.3 and R.sub.6 is independently hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 each of R.sub.4 and R.sub.7 is independently hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, with the provisos that not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, not more than one of R.sub.2 and R.sub.3 is benzyloxy, not more than one of R.sub.5 and R.sub.6 is trifluoromethyl, not more than one of R.sub.5 and R.sub.6 is phenoxy, and not more than one of R.sub.5 and R.sub.6 is benzyloxy, PA1 X is --(CH.sub.2).sub.m --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 --CH.dbd.CH--, wherein m is 0, 1, 2 or 3, and PA1 Z is ##STR19## wherein R.sub.10 is hydrogen or C.sub.1-3 alkyl, and R.sub.11 is hydrogen, R.sub.12 or M, wherein PA1 R.sub.12 is a physiologically acceptable and hydrolyzable ester group, and PA1 M is a cation, PA1 with the provisos that (i) the --X--Z group is in the 4- or 5-position of the pyrazole ring, and (ii) the R.sub.1 group and the --X--Z group are ortho to each other. PA1 R.sub.2 =alkyl, cycloalkyl, adamantyl-1 or R.sub.7, R.sub.8, R.sub.9 -substituted phenyl (gp. B); PA1 R.sub.3 =H, alkyl, cycloalkyl, adamantyl-1, styryl or R.sub.10, R.sub.11, R.sub.12 -substituted phenyl (gp, C); PA1 X=--(CH.sub.2).sub.m --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 --CH.dbd.CH--; PA1 m=0-3; PA1 Z=--CH(OH)--CH.sub.2 --C(R.sub.13)(OH)--CH.sub.2 --COOR.sub.14 (gp. a), --Q--CH.sub.2 C(R.sub.13)(OH)--CH.sub.2 --COOR.sub.14 (gp. c) or a gp. of formula (b): ##STR21## Q=CO or --C(OR.sub.15).sub.2 --; R.sub.15 =primary or sec. alkyl; each R.sub.15 being the same; PA1 or R.sub.15 +R.sub.15 =(CH.sub.2).sub.2 or (CH.sub.2).sub.3 ; PA1 R.sub.13 =H or 1-3C alkyl; PA1 R.sub.14 =H, R.sub.16 or M; PA1 R.sub.16 =ester gp; PA1 M=cation; PA1 provided that Z may be gp. (c) only when X is CH.dbd.CH or CH.sub.2 --CH.dbd.CH and/or when R.sub.13 =1-3C alkyl; PA1 R.sub.4, R.sub.7 and R.sub.10 =1-3C alkyl, n-, i- or t-butyl, 1-3C alkoxy, n- or i-butoxy, CF.sub.3, F, Cl, Br, phenyl, phenoxy or benzyloxy; PA1 R.sub.5, R.sub.8 and R.sub.11 =H, 1-3C alkyl, 1-3C alkoxy, CF.sub.3, F, Cl, Br, COOR.sub.17, N(R.sub.19).sub.2, phenoxy or benzyloxy; PA1 R.sub.17 =H, R.sub.18 or M; PA1 R.sub.18 =1-3C alkyl, n, i- or t-butyl or benzyl; PA1 R.sub.19 =alkyl; PA1 R.sub.6, R.sub.9 and R.sub.12 =H, 1-2C alkyl, 1-2C alkoxy, F or Cl; provided that PA1 or R+R.sub.1 =(CH.sub.2).sub.m or (Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 ; PA1 m=2-6; PA1 R.sub.o =1-6C alkyl, 3-7C cycloalkyl or R.sub.4, R.sub.5, R.sub.6 -substituted phenyl; PA1 R.sub.2, R.sub.4 =H, 1-4C alkyl, 1-4C alkoxy (except t-butoxy), CF.sub.3, F, Cl, phenoxy or benzyloxy; PA1 R.sub.3 and R.sub.5 =H, 1-3C alkyl, 1-3C alkoxy, CF.sub.3, F, Cl, phenoxy or benzyloxy; PA1 R.sub.6 =H, 1-2C alkyl, 1-2C alkoxy, F or Cl; PA1 provided that there may only be one each of CF.sub.3, phenoxy or benzyloxy on each of the phenyl and indene rings; PA1 X=(CH.sub.2).sub.n or --(CH.sub.2).sub.q --CH.dbd.CH(CH.sub.2).sub.q --; PA1 n=1-3; PA1 both q's=0, or one is 0 and the other is 1; PA1 Z=--Q--CH.sub.2 --C(R.sub.10)(OH)--CH.sub.2 COOH, in free acid form or in the form of an ester or delta-lactone or salt; PA1 Q=CO, --C(OR.sub.7).sub.2 -- or CHOH; PA1 R'.sub.7s =the same primary or secondary 1-6C alkyl, or together are (CH.sub.2).sub.2 or (CH.sub.2).sub.3 ; PA1 R.sub.10 =H or 1-3C alkyl; PA1 provided that Q may be other than CHOH only when X is CH.dbd.CH or CH.sub.2 --CH.dbd.CH and/or R.sub.10 is 1-3C alkyl. PA1 R.sub.2 and R.sub.3 =H, Cl, Br, CN, CF.sub.3, phenyl, 1-4C alkyl, 2-8C carboalkoxy, --CH.sub.2 OR.sub.6 or --CH.sub.2 OCONHR.sub.7 ; PA1 R.sub.6 =H or 1-6C alkanoyl; PA1 R.sub.7 =alkyl or phenyl optionally substituted by Cl, Br or 1-4C alkyl; PA1 or R.sub.2 and R.sub.3 together=--(CH.sub.2).sub.n --, --CH.sub.2 OCH.sub.2 --, --CON(R.sub.8)CO-- or --CON(R.sub.9)N(R.sub.10)CO--; PA1 n=3 or 4; PA1 R.sub.8 =H, 1-6C alkyl, phenyl or benzyl; PA1 R.sub.9 and R.sub.10 =H, 1-4C alkyl or benzyl; PA1 R.sub.4 =1-4C alkyl, cyclopropyl, cyclobutyl or CF.sub.3. PA1 R.sub.1, R.sub.2 and R.sub.3 are, e.g., hydrogen, chloro, bromo, fluoro, C.sub.1 -alkyl, phenyl, substituted phenyl or OR.sub.7 in which R.sub.7 is, e.g., hydrogen, PA1 C.sub.2-8 alkanoyl, benzoyl, phenyl, substituted phenyl, C.sub.1-9 alkyl, cinnamyl, C.sub.1-4 haloalkyl, allyl, cycloalkyl-C.sub.1-3 alkyl, adamantyl-C.sub.1-3 -alkyl, or phenyl C.sub.1-3 alkyl; PA1 R.sup.4, R.sup.5 and R.sup.6 are hydrogen, chloro, bromo, fluoro or C.sub.1-3 alkyl; and PA1 X is, e.g., hydrogen, C.sub.1-3 alkyl, a cation derived from an alkali metal or is ammonium. PA1 R.sub.3 and R.sub.4 =H, lower alkyl or optionally substituted aryl or aralkyl. PA1 E is --CH.sub.2 CH.sub.2, --CH.dbd.CH--, or --(CH.sub.2).sub.r --; and PA1 Z is
X is --(CH.sub.2).sub.n -- or --CH.dbd.CH-- (n=0, 1, 2 or 3), Z is ##STR7## wherein R.sub.6 is hydrogen or C.sub.1-3 alkyl in free acid form or in the form of a physiologically-hydrolysable and -acceptable ester or a .delta. lactone thereof or in salt form.
GB 2162-179-A discloses naphthyl analogues of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure ##STR8## wherein R.sub.1 =1-3C alkyl; Z is a gp. of formula Z.sub.1 or Z.sub.2 : ##STR9## R.sub.7 =H, a hydrolysable ester gp. or a cation.
European Patent No. 164-698-A discloses preparation of lactones useful as anti-hypercholesterolemic agents by treating an amide with an organic sulphonyl halide R.sup.5 SO.sub.2 X, then removing the protecting group Pr. ##STR10## wherein X=halo;
Anderson, Paul Leroy, Ger. Offen. DE 3,525,256 discloses naphthyl analogs of mevalonolactones of the structure ##STR13## wherein R.sup.1 is alkyl, Z=Q, Q.sup.1 ; R.sup.7 =H, or a hydrolyzable ester group useful as inhibitors of cholesterol biosynthesis and in treatment of atherosclerosis.
WO 8402-903 (based on U.S. application Ser. No. 460,600, filed Jan. 24, 1983) filed in the name of Sandoz A. G. discloses mevalono-lactone analogues useful as hypolipoproteinaemic agents having the structure ##STR14## wherein the two groups Ro together form a radical of formula ##STR15## wherein R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
U.S. Pat. No. 4,613,610 to Wareing (assigned to Sandoz) discloses a series of 7-pyrazolo-3,5-dihydrohept-6-enoic acid HMG-CoA reductase inhibitors of the structure ##STR18## wherein R.sub.1 is C.sub.1-6 alkyl not containing an asymmetric carbon atom,
WO 8607-054A (Sandoz-Erfindungen) discloses imidazole analogues of mevalonolactone, useful for treating hyperlipoproteinaemia and atherosclerosis, which have the formula ##STR20## R.sub.1 =alkyl, cycloalkyl, adamantyl-1 or R.sub.4, R.sub.5, R.sub.6 -substituted phenyl (gp. A);
(1) not more than one substituent of each of gps. A, B and C is CF.sub.3, not more than one substituent of each of gps. A, B and C is phenoxy, and not more than one substituent of each of gps, A, B and C is benzyloxy; PA2 (2) when Z is gp. (c; Q=C(OR.sub.15).sub.2), the compound is in free base form and either (i) R.sub.14 is R.sub.16 and each R.sub.17 is independently R.sub.18 or (ii) R.sub.14 is M and each R.sub.17 is independently R.sub.18 or M; and PA2 (3) when R.sub.14 and/or at least one R.sub.17 is M, the compound is in free base form. PA2 1) ##STR36## wherein X is --O-- or --NR.sup.9 wherein R.sup.9 is hydrogen or C.sub.1-3 alkyl; PA2 2) ##STR37## wherein R.sup.10, R.sup.11 and R.sup.12 are independently, e.g., hydrogen, halogen or C.sub.1-4 alkyl; PA2 3) ##STR38## wherein n is 0-2 and R.sup.14 is halo or C.sub.1-4 alkyl; or 4) ##STR39##
Unless otherwise stated, all "alkyl" gps. are 1-6C and do not contain an asymmetric C; and "cycloalkyl" has 3-7C.
WO 8603-488-A (Sandoz AG) discloses indene analogues of mevalolactone, useful as hypolipoproteinaemia and anti-atherosclerotic agents, in free acid form or in the form of an ester or delta-lactone or in salt form which have the formula ##STR22## R=H or primary or secondary 1-6C alkyl; R.sub.1 =primary or secondary 1-6C alkyl;
U.S. Pat. No. 4,647,576 to Hoefle et al (Warner Lambert) discloses new C- and N-substituted pyrrole(s), useful as hypolipidaemic and hypocholesterolaemic agents, which have the formula ##STR23## X=--CH.sub.2 --, --CH.sub.2 CH.sub.2 -- or --CH(CH.sub.3)CH.sub.2 --; R.sub.1 =1- or 2-naphthyl; cyclohexyl; norbornenyl; phenyl optionally substituted by F, Cl, OH, CF.sub.3, 1-4C alkyl, 1-4C alkoxy or 2-8C alkanoyloxy; 2-, 3- or 4-pyridinyl or their N-oxides; or ##STR24## R.sub.5 =1-4C alkyl; hal=chloride, bromide or iodide;
European patent application 0 221 025 A1 (Sandoz AG) discloses heterocyclic analogs of mevalonolactone and derivatives thereof having the formula ##STR25## wherein Ra is a group --X--Z, Rb is R.sub.2, Rc is R.sub.3, Rd is R.sub.4 and Y is a group ##STR26## or Ra is R.sub.1, Rb is a group --X--Z, Rc is R.sub.2, Rd is R.sub.3 and Y is O, S or a group ##STR27## R.sub.1, R.sub.2, R.sub.3 and R.sub.4 independently are C.sub.1-4 alkyl not containing an asymmetric carbon atom, C.sub.3-7 cycloalkyl or a ring ##STR28## or in the case of R.sub.3 and R.sub.4 additionally hydrogen or for R.sub.3 when Y is O or S ##STR29## whereby R.sub.17 is hydrogen or C.sub.1-3 alkyl and R.sub.18 and R.sub.19 are independently hydrogen, C.sub.1-3 alkyl or phenyl; each R.sub.5 is independently hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy; each R.sub.4 is independently hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy and each R.sub.7 is independently hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro with the proviso that there may only be one each of trifluoromethyl, phenoxy or benzyloxy in each ring A present. X is (CH.sub.2).sub.m or (CH.sub.2).sub.q CH.dbd.CH(CH.sub.2).sub.q, m is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1.
Z is ##STR30## wherein R.sub.9 is hydrogen or C.sub.1-3 alkyl, in free acid form or in the form of an ester of .beta.-lactone thereof or in salt form as appropriate which compounds are indicated for use as hypolipoproteinemic and anti-atherosclerotic agents.
Tetrahedron Letters, 29, 929, 1988, discloses the synthesis of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor of the structure ##STR31## where R is Na or C.sub.2 H.sub.5.
European patent application 127,848-A (Merck & Co, Inc.) discloses derivatives of 3-hydroxy-5-thia-.omega.-aryl-alkanoic acids having the structural formula: ##STR32## wherein Z is: ##STR33## n is 0, 1 or 2; E is --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 --, --CH.dbd.CH--CH.sub.2 --; or --CH.sub.2 --CH.dbd.CH--;
Those compounds have antihypercholesterolemic activity by virtue of their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and antifungal activity.
French patent application 2,596,393 A filed on Apr. 1, 1986 (Sanofi SA) discloses 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives including salts thereof which are useful as hypolipaemic agents and have the formula: ##STR34## wherein R.sub.1 and R.sub.2 =H, lower alkyl or optionally substituted aralkyl;
These comounds are disclosed as giving greater reductions in cholesterol, triglyceride and phospholipid levels than meglutol.
European patent application 142, 146-A (Merck & Co., Inc) discloses mevinolin-like compounds of the structural formula: ##STR35## wherein: R.sup.1 is, e.g., hydrogen or C.sub.1-4 alkyl;
R.sup.7 is C.sub.2-8 alkyl; and PA3 R.sup.8 is hydrogen or CH.sub.3 ;
These compounds are HMG-CoA reductase inhibitors.